The present invention relates to a perfluoroalkylation technique and especially a reactant, a compound and a process for the perfluoroalkylation of a nucleophile, and to the derivatives thus obtained. It relates more particularly to the use of the homolytic scission of certain chalcogen esters with relatively heavy chalcogens, that is to say of an atomic rank at least equal to that of sulphur.
Thus, the field of the invention is that of the synthesis of compounds which are perhaloalkylated and/or acylated:
either by grafting of perhaloalkyl and/or acyl radicals on to substrates, at least partially organic and of various kinds, the said radicals being supplied by perhaloalkylating and/or acylating agents,
or by direct autotransformation of perhaloalkylating agents.
The present invention also relates to a process for obtaining perhalogenated, in particular perhaloalkylated and/or acylated compounds and to perhaloalkylated and/or acylated thioethers.
The halogen considered more precisely but without any limitation being implied is fluorine, because of the great interest which exists in employing it as a substituent in many industrial products such as colorants, polymers and pharmaceutical and agrochemical compounds. It is well known, in fact, that fluorine is an inducer of lipophilicity in biologically active molecules.
Moreover its electronegativity and its relatively small size are positive factors in relation to:
the absorption of light by colorants,
the stability, solubility and mechanical and electrical properties of polymers,
and the biological properties of certain pharmaceutical and/or agrochemical molecules.
Bearing in mind the scientific and technical interest of the trifluoromethyl substituent, especially in the pharmaceutical and the agrochemical fields, many methods of trifluoromethylation have already been proposed.
Among these, direct trifluoromethylation according to an electrophilic, nucleophilic and/or radical mechanism is that most worthy of interest from the technical and industrial standpoint.
Techniques for trifluoromethylation by a radical have the advantage of often making it possible to operate in very mild conditions.
To be sure, using this route, the perfluoroalkylation with the aid of perfluoroalkyl iodides such as CF3I is known. These compounds react with various substrates thermally, under irradiation or in the presence of a catalytic quantity of a radical initiator such as benzoyl peroxide or azobisisobutyronitrile (AIBN). Perfluoroalkyl iodides are costly products and rarely available on an industrial scale.
Moreover, the reactions involved are liable to give rise, as by-products, to iodine-containing products known to be toxic, of the CF3xe2x80x94CH2xe2x80x94CH2xe2x80x94I type.
Derivatives of perfluoroalkanesulphonic acids which are also suitable for a radical route are themselves also costly and still rarely available on an industrial scale.
Nitrosotrifluoromethane derivatives can also be employed, but suffer from the disadvantage of being toxic and hazardous to synthesize.
Perfluoroalkanoic acids and their derivatives, such as trifluoroacetic acid, could possibly have been employed as perhaloalkylating agents. It has been found, however, that they are difficult to convert into the .CF3 radical. The electrochemical oxidation used for this purpose requires, in fact, very high voltages and large excesses of this reactant. The industrial feasibility of the process involving these compounds is therefore not established.
Trifluoromethanethiol (CF3SH) and trifluoromethanesulphenyl chloride CF3SCl are known as being reactive agents for trifluoromethylthiolation. However, they have the disadvantage of being gaseous and highly toxic.
In practice, the most common trifluoromethylating agent is bromotrifluoromethane (CF3Br). This industrial product is employed as a fire-extinguishing agent, especially in aircraft and computer rooms. It is at present one of the largest sources of trifluoromethyl radicals.
CF3Br can be reduced monoelectronically to give .CF3, a radical capable of being trapped, either by nucleophilic substrates, reducing agents and initiators, such as thiolates, thiophenates, selenophenates, stabilized carbanions or enamines, or by a reducing agent of the SO2xe2x88x92. type.
By way of example of a conversion, according to the abovementioned technique, of disulphide substrates giving rise to trifluoromethylated alkyls or aryl sulphides, reference will be made to the paper by Clavel et al.: Phosphorus, Sulfur and Silicon, 1991, vol. 59, p. 129-132. The paper by Wakselman et al., J. Chem. Soc., Chem. Commun., 1984, p. 793-794, gives an illustration of the trifluoromethylation of thiophenols with the aid of CF3Br.
Alternatively, .CF3 can be generated with the aid of an oxidizing agent of the tert-butyl hydroperoxide (t-BuOOH) type and of sodium trifluoromethanesulphinate (CF3SO2Na), itself obtained from bromotrifluoromethane and sodium dithionite. In these conditions disulphides are converted to trifluoromethyl thioethers (RSCF3) (cf. Clavel and al.: Phosphorus, Sulfur and Silicon, 1991, vol. 59, pages 169-172), aromatic compounds are trifluoromethylated (cf. Langlois and al.: Tetrahedron Letters, 1991, vol. 32, No. 51, p. 7525-7528) and enol esters produce trifluoromethyl ketones (cf. Langlois and al.: Tetrahedron Letters, 1992, vol. 33, No. 10, p. 1291-1294).
The problem related to these known techniques employing bromotrifluoromethane as source of .CF3 has to do with the difficulty of handling this gas. What is more, it is a product which is bound to be prohibited by the international regulations dealing with the environment, because of its presumed harmful effects on the environment, especially because of the greenhouse effect which it allegedly produces, and hypothetical effects on the ozone layer.
This will therefore give rise to a considerable demand for radical trifluoromethylating agents which are convenient to use, nontoxic, easily available and inexpensive.
Thus, one of the objectives of the present invention is to provide a process for obtaining perhalogenated, in particular perhaloalkylated and/or acylated, compounds in which advantageous substitutes for bromotrifluoromethane are used.
Another aim of the present invention is to provide a reactant of the above type which allows a perfluoro radical to be grafted on to an electrophile.
Another aim of the present invention is to provide compounds which are capable of being employed for the above reactants and/or in the above process.
Another aim of the present invention is to provide derivatives which are capable of being obtained by the reactants and process of the above type.
The Applicant Company has succeeded in developing such a reactant, which is characterized in that it comprises, for successive or simultaneous addition:
a compound of formula (I):
Rfxe2x80x94M(X)(Z)nxe2x80x94Yxe2x80x94R;
with R denoting a carbon-containing radical, advantageously of at most 15 preferably 10 carbon atoms, preferably chosen from alkyls, aryls, acyls, thioacyls [such as the hydrocarbyl-chalcogenylacyls (and especially carbonyls) (the preferred chalcogens here are sulphur and oxygen), especially aryloxyacyls, alkoxyacyls and in particular aryloxycarbonyls, alkoxycarbonyls and aryloxythiocarbonyls, alkoxythiocarbonyls or their homologues when the oxygens are completely or partially replaced with sulphur];
with Rf, advantageously exhibiting at most 20 carbon atoms, preferably at most 15 carbon atoms,
denoting a radical of formula (II):
[R2xe2x80x94(C)pxe2x80x94][R1xe2x80x94(C)m]CFxe2x80x94
where R1 and R2, which are similar or different, denote a light halogen atom, fluorine or chlorine, preferably fluorine, a carbon-containing radical
where m is zero or an integer chosen-within the closed interval from 0 to 12, advantageously at most equal to 8 and preferably at most equal to 6;
where p is zero or an integer chosen within the closed interval from 0 to 12, advantageously at most equal to 6, preferably at most equal to 4;
where s, which are similar or different, denote perhalogenated, advantageously perfluorinated, radicals, chlorine or preferably fluorine atoms; with the condition that when m and/or p are equal to zero, R1 is electron-withdrawing, advantageously a fluorine or chlorine atom, preferably a fluorine atom;
with n denoting zero or 1;
with M denoting a metalloid chosen from carbon and the chalcogens of a rank higher than oxygen;
with X, Y and Z, which are similar or different, denoting a chalcogen;
a source of radicals.
When M is carbon n is equal to zero.
Thus R is advantageously a substituted or unsubstituted, linear or branched aliphatic or alicyclic radical, preferably alkyl, including aralkyl, aralkenyl, aralkynyl, alkenyl and alkynyl, and aryl.
R may also be a radical of formula Rfxe2x80x94M(X)(Z)axe2x80x94 where Rf, M, X, Y, Z and n have the same meaning as set out above, without this meaning that the molecule is necessarily symmetrical.
It is advantageous that X, Y and, when n is other than zero, Z are not all oxygens in the same single molecule.
It should be remembered that the expression xe2x80x9chydrocarbylchalcogenylxe2x80x9d is a radical of structure Raxe2x80x94Yxe2x80x3xe2x80x94 where Raxe2x80x94 is a hydrocarbon radical, that is to say one containing at least hydrogen and carbon and in which the atom carrying the bond (here with Yxe2x80x3) is a carbon, and where Yxe2x80x3 is a chalcogen (oxygen, sulphur, selenium, tellurium). Ra is advantageously an alkyl [optionally substituted and especially halogenated (including perhalogenated and especially perfluorinated)] or an optionally substituted aryl.
According to the present invention, if the intention is to avoid interfering reactions, it is highly desirable that R should be chosen so that the radical R is only slightly stable or unstable; thus, benzyls, tertiary alkyls and any radical whose corresponding free radical is equally, or more, stable than those mentioned above, are to be avoided.
The compounds of formula (I) may be employed in such a way and in such conditions that they, and especially the thioloesters of formula (I), can generate free radicals.
The said radical-generator may be an actinic source. The process according to the invention consists in reacting the thioloester of formula (I) with an at least partially organic unsaturated substrate, preferably under irradiation at a wavelength of between 200 and 800 nanometers; the said radical-generator is then a source of radiation of wavelength included between 200 and 800 nm and preferably between 210 and 600 nm (nanometers). To obtain the best results it is recommended to adopt the wavelength corresponding to the absorption maximum of the chromophore functional group xe2x80x94M(X)(Z)aYxe2x80x94.
The said radical-generator may also be a chemical source of free radicals. As already mentioned above, it is possible to employ the compounds of formula (I) in such a way and in such conditions that they, and especially the thioloesters of formula (III), can generate free radicals.
According to an advantageous method of the invention, the said mechanisms involve an initiator, which may be of chemical nature [for example acyl peroxides, being symmetrical, mixed and/or hydrogen peroxides (the most common of which is the benzoyl compound), alkyl peroxides (in general tertiary, the most widely employed of which are the tert-butyl compounds), or azo derivatives (such as azobisisobutyronitrile=AIBN)], advantageously in the presence of stannane (especially hydrostannane) and/or of silanes (especially hydrosilane); the stannanes and especially the distannanes (such as Bu3SnSnBu3) may be employed alone.
Advantageously the reactant additionally comprises a solvent.
The solvent may also consist of an excess of one of the reactants.
When actinic initiation is employed, to is prevent the radiation energy hxcexd initiating the radical reaction from being absorbed by the solvent at the expense of the thioloester (I), it is important to choose the solvent so that it has a transmittance higher than or equal to 50%, preferably to 70%, and, still more preferably, to 90%, at the working wavelength.
Accordingly, in accordance with the invention, when actinic initiation is present, the solvent is preferably selected from the following compounds: acetonitrile, ethanol, butanol, dichloromethane, cyclohexane, cyclopentane, 1,2-dichloroethane, 2,2-dimethylbutane, n-heptane, n-hexane, methanol, 2-methylbutane, isooctane, n-pentane, 2-propanol, 1,2,2-trichlorotrifluoroethane, 2,2,2-trifluoroethanol or a mixture of these.
When another kind of initiation is employed it is appropriate to employ solvents which are inert towards the compounds (I) as in all cases, but also towards initiators that may be physical (radiation, temperature for thermolysis radicals produced from chemical initiators).
If attention is now turned to the compounds of formula (I):
Rfxe2x80x94M(X)(Z)nxe2x80x94Yxe2x80x94R;
It is desirable that at least one, preferably two compatible conditions hereinafter should be fulfilled:
Y should be a heavy chalcogen advantageously chosen from selenium and sulphur, preferably a sulphur;
Z is a light chalcogen advantageously chosen from oxygen and sulphur, preferably a sulphur;
X is a light chalcogen advantageously chosen from oxygen and sulphur,. preferably oxygen;
M is a carbon atom, n is zero, X is oxygen and Y is sulphur or selenium;
M is a sulphur or selenium atom, n is one, X is oxygen and Y is sulphur or selenium.
It is advantageous that X, Y and, when n is other than zero, Z should not all be oxygen in the same single molecule.
Thus, in the course of the study which led to the present invention, it was found that some of the compounds which may be used in the reactant described above had never been described, have had to be synthesized and were new.
Thus, another aim of the present invention is to provide a compound of the above type, as well as a process for the synthesis of these compounds. These aims and others which will appear below are met by means of compound(s) of formula (I)
Rfxe2x80x94M(X)(Z)nxe2x80x94Yxe2x80x94R;
with R denoting a hydrocarbon radical, advantageously of at most 10 carbon atoms, preferably chosen from alkyls and aryls;
with Rf denoting a radical of formula:
[R2xe2x80x94(C)pxe2x80x94][R1xe2x80x94(C)axe2x80x94]CFxe2x80x94
where R1 and R2, which are similar or different, denote a light halogen atom, fluorine or chlorine, preferably fluorine, a carbon-containing radical
where m is zero or an integer included between 0 and 12;
where p is zero or an integer included between 0 and 12;
where the , which are similar or different, denote perhalogenated, advantageously perfluorinated radicals, chlorine or preferably fluorine atoms; on the condition that when m and/or p are equal to zero, R1 is electron-withdrawing, advantageously a fluorine or chlorine atom, preferably a fluorine atom;
with n denoting zero or 1;
with M denoting a metalloid chosen from carbon and the chalcogens of a rank higher than oxygen;
with Y denoting a sulphur or a selenium;
with X and Z, which are similar or different, denoting a chalcogen.
R1 is a carbon-containing radical chosen from alkyls and aryls.
Rf is a carbon-containing radical of at most 20 carbons, preferably of at most 15 carbons. The compounds according to the present invention are particularly advantageous where their Rf comprise (s) more than one carbon atom and, above all, more than three.
It is desirable that there should be at least one chalcogen heavier than oxygen among M and X.
The compounds which have at least one selenium atom as M, X, Y, Z are particularly original. The compounds where M is a chalcogen and where n is equal to 1 have the characteristic of giving only one perfluoroalkylation, which is an advantage when it is this reaction that is required. Finally, the derivatives where R corresponds to the formula Rfxe2x80x94M(X)(Z)nxe2x80x94 are particularly advantageous.
Another aim of the present invention is to provide a process which can be used for grafting perhalogenated, advantageously perfluorinated groups of the above Rf type. This graft may be an autograft, that is to say a graft on a substrate consisting of a compound or a decomposition product of a compound of formula (I):
Rfxe2x80x94M(X)(Z)nxe2x80x94Yxe2x80x94R;
This aim and others which will appear in what follows are met by means of a process comprising at least one stage in which the said compound exhibiting at least one nucleophilic functional group is placed in contact with a reactant described above.
The process according to the invention will be described further by frequently employing the thioloesters as a paradigm. These thioloesters are perfluoro compounds which have the following formula:
Rfxe2x80x94COxe2x80x94Sxe2x80x94Rxe2x80x83xe2x80x83(III)
in which:
Rf is defined above and advantageously denotes the radical:
xe2x80x94CnF(2n+1)
where n is at least equal to 1, often equal to 1,
and R is a substituted or unsubstituted, linear or branched aliphatic or alicyclic radical, preferably alkyl including alkenyl, alkynyl, aryl, aralkyl, aralkenyl or aralkynyl.
It is practical that the starting materials, according to the invention, should consist of compounds of CF3COSR type, because these are compounds that are very easily accessible from trifluoroacetic anhydride and a thiol RSH.
In addition, the process according to the invention does not involve the handling of hazardous and toxic products, nor does it generate them.
This perhalo, preferably perfluoro thioloester can be likened to a supplier of the radical Rf, often corresponding to [CnF(2n+1)] for obtaining the compounds which are aimed at.
The process according to the invention can especially be envisaged according to two main routes:
the first of these can be summarized as a direct radical conversion of a compound of formula (I) and especially the thioloester (III) to a perfluoroalkyl thioether (or S-alkyl perfluoro compound) (CnF(2n+1)xe2x80x94Sxe2x80x94R), by decarbonylation (or desulphonylation or equivalents),
the second consists essentially in reacting, by a radical route, a compound of formula (I) and especially the thioloester (III) with at least one substrate, in such a way that at least one CnF(2n+1) and/or CnF(2n+1)CO radical is grafted onto the said substrate.
In accordance with an advantageous method of the invention, the said mechanisms involve an initiator, which may of chemical nature (e.g. benzoyl peroxide, tert-butyl peroxide, stannanes such as Bu3SnSnBu3 or azobisisobutyronitrile=AIBN) and/or of physical nature (thermal route and/or irradiation).
In the case of both routes of the process according to the invention a preferred embodiment consists of a thermolysis of the compound (I) between, preferably, 350 and 650xc2x0 C. (and more preferably 400 to 600xc2x0 C.) in, for example, an iron, quartz or glass tube (optionally filled with crushed glass).
In the case of both routes of the process according to the invention, another preferred embodiment consists of a photolysis in a reaction medium optionally containing an organic solvent, at a wavelength and at a reaction temperature TR; is, advantageously, included between 200 and 800 nm and, preferably, between 210 and 600 nm.
To prevent the radiation energy hxcexc initiating the radical reaction from being absorbed by the solvent at the expense of the thioloester (I), it is important to choose the solvent so that it has a transparency greater than or equal to 50%, preferably to 70% and, still more preferably, to 90%, at the working wavelength.
Accordingly, in accordance with the invention the solvent is preferably selected from the following compounds: acetonitrile, ethanol, butanol, dichloromethane, cyclohexane, cyclopentane, 1,2-dichloroethane, 2,2-dimethylbutane, n-heptane, n-hexane, methanol, 2-methylbutane, isooctane, n-pentane, 2-propanol, 1,2,2-trichlorotrifluoroethane, 2,2,2-trifluoroethanol or a mixture of these.
It is self-evident that the invention is not restricted to a method of activation by irradiation, especially by UV irradiation. Any other type of radical initiation can, in fact, be envisaged: heat, radical auxiliary (cf. above).
In accordance with an advantageous characteristic of the invention the solvent is chosen so that its boiling temperature at a given pressure is at least equal to, preferably substantially equal to, the reaction temperature TR.
To obtain perhalo compounds which are in particular perfluoroalkylated and/or S-alkylated it is preferable to provide for a reaction temperature TR higher than or equal to 20xc2x0 C. and, still more preferably, higher than or equal to 35xc2x0 C. In practice TR may thus be of the order of, for example, 40xc2x0 C.
On the other hand, when perhaloacylated, in particular perfluoroacylated, compounds are aimed at, TR is ideally lower than or equal to 30xc2x0 C., preferably to 25xc2x0 C. and, still more preferably, is of the order of 20xc2x0 C.
Within the scope of the second route for implementing the process of the invention the substrate may be a disulphide of the following formula:
Rxe2x80x2xe2x80x94Sxe2x80x94Sxe2x80x94Rxe2x80x3xe2x80x83xe2x80x83(IV)
The radicals Rxe2x80x2 and Rxe2x80x3 in the compound (IV) and the radical R in the compound (I) may be identical or different from each other. They are preferably identical and correspond to the definition of R given above.
By way of examples of radicals R, Rxe2x80x2 and Rxe2x80x3 there may be mentioned xe2x80x94CH2CH2COOCH2CH3, phenyl, chlorophenyl, tert-butyl, n-butyl, cyclohexyl, benzyl, methyl, isopropyl, n-propyl, ethyl and octyl.
The preparation of thioethers CnF(2n+1)SR (V) with the aid of a disulphide substrate (IV) benefits from a better yield than the direct conversion of the thioloester (I) to thioether (V) according to the first route of implementing the process according to the invention.
According to an alternative form of its second route of implementation, the process according to the invention consists in reacting the a compound of formula (I) and especially the thioloester of formula, (III) with an at least partially organic unsaturated substrate, preferably under irradiation at a wavelength included between 200 and 800 nm, at a reaction temperature TR and in an organic medium as defined above.
The result is a perhalo, preferably perfluoro, alkyl product in the case of TR40-50xc2x0 C. and a perhalo, preferably perfluoro, acyl product in the case of TR20-30xc2x0 C.
The olefinic substrates which can be envisaged for this perhaloalkylation or acylation and in particular for this trifluoromethylation (CF3xe2x80x94) or trifluoroacetylation (CF3xe2x80x94COxe2x80x94) with the aid of thioloesters (I) of trifluoroacetic acid (CF3COSR) are, especially, alkenes, cycloalkenes, (cyclo)alkynes, aromatics or mixtures of these.
The olefinic substrate is preferably characterized in that it is formed by at least one of the materials belonging to at least one of the following chemical classes:
alkenes and alkynes which are not functionalized on the unsaturation,
ethers and enol esters,
enol perhalocarboxylates,
vinyl sulphides,
enamines,
enoxy, enethio and enaminostannanes,
allystannanes,
enoxy, enethio and enaminosilanes,
allylsilanes.
With regard to the stoichiometry which is specific to the preferred embodiments of the process according to the invention (2nd route), it should be considered that the molar ratio of the compound of formula (I) to the substrate is advantageously between 0.1 and 10, preferably between 0.5 and 2 and, still more preferably, between 0.9 and 1.1.
When the reactant according to the invention is reacted with a carbon-carbon double bond, the resulting free radical can proceed in various ways and especially may combine with the sulphur-containing radicals of the media or else abstract a hydrogen from a compound carrying it. If it is desired to promote the hydrogen abstraction reaction (because it gives the addition of the perfluoroalkyl to one of the carbons and of a hydrogen to the other) it is appropriate to introduce into the reaction mixture products such as diphenylmethane, toluene, xylenes or even allyls, which are capable of donating a hydrogen atom to a free radical.
In accordance with the invention the compounds of formula (I) are novel agents for radical perhaloalkylation and/or -S-alkylation and/or acylation, the halogen considered being preferably fluorine. These thioloesters (I) have the advantage of being easy to prepare and to use, economical and ecologically tolerable.
It is no doubt superfluous to observe that only those compounds according to the formula in which M is carbon give acylations.
The perhalo(fluoro)alkyl thioethers and the perhalo(fluoro)alkylated or acylated products obtained by the process according to the invention are notably capable of being exploited in the pharmaceutical or plant-protection sector.
However, one of the most innovative and most advantageous applications consists in making derivatives which are at the same time silanated and have at least one perfluoro branching.
These compounds, which are difficult to prepare, offer a great advantage. By employing the technique according to the present invention it is possible in particular to carry out such a synthesis either by perfluorination of a derivative which has a silane functional group and an unsaturation in a nonvinyl position or by perfluorinating a compound which has two double bonds and then silylating the remaining functional group.
Thus, according to the invention it is particularly advantageous to subject to the process according to the invention compounds of formula (V) below:
(R4)(R5)Cxe2x95x90C(R6)(R7)
with R4, R5, R6 and R7, which are similar or different, chosen from hydrogen, hydrocarbon radicals and especially from alkyls, including cycloalkyls and aralkyls, and from aryls, with the condition that at least one of the R4, R5, R6 and R7 denotes:
a monovalent radical carrying a silicon atom at a distance from the free valency of at least one, advantageously of at least two, carbon atoms;
a monovalent radical carrying a nonaromatic double bond in a nonvinyl position with the free valency.
The radicals R4 and R5 may be joined to their corresponding radical (that is to say in a cis position) R6 or R7 to form one or two advantageously nonaromatic rings. It is preferable, however, that there should be only one ring thus formed.
The products thus formed are of formula VI:
(R4)(R5)CHxe2x80x94C(Rf)(R6)(R7)xe2x80x83xe2x80x83(VI)
or
(R4)(R5)C(SR)xe2x80x94C(Rf)(R6)(R7)xe2x80x83xe2x80x83(VII)
in which R4, R5, R6 and R7 have the same value as in formula (V).
Rf advantageously has at least two, preferably at least four carbons. In addition, p+m is advantageously at least equal to two, preferably at least to four.
It is desirable that only one of R4, R5, R6 and R7 should carry a nonaromatic double bond or one (or more) silicon atom(s).
As the perfluoroalkylation reaction is highly sensitive to steric hindrance of the substrate, it is preferable that among the radicals R4, R5, R6 and R7 there should be at least one, preferably at least two which denote hydrogen atoms.
It is preferable that among the radicals R4, R5, R6 and R7 there should be at most one which denotes a hindering radical. A hindering radical is intended in the present description to mean a radical in which the atom carrying free valency should additionally carry two and, above all, three branchings of at least one carbon.
Bearing the above in mind, it should be reported that the reaction is highly selective between the double bonds which are not highly hindered and those which are.